Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

DNA methylation and human disease

Nature Reviews Genetics volume 6, pages 597–610 (2005)Cite this article

Key Points

  • DNA methylation is an epigenetic modification of DNA that is important for the normal regulation of transcription, embryonic development, genomic imprinting, genome stability and chromatin structure.

  • DNA methylation is controlled by DNA methyltransferases, methyl-CpG binding proteins and other chromatin-remodelling factors.

  • Aberrations in the DNA methylation system have an important role in human disease.

  • DNA methylation patterns are globally disrupted in cancer, with genome-wide hypomethylation and gene-specific hypermethylation events occurring simultaneously in the same cell.

  • Loss of normal imprinting contributes to several inherited genetic diseases in humans. These diseases include Beckwith–Wiedemann, Prader–Willi, and Angelman syndromes, Albright hereditary osteodystrophy (AHO) and pseudohypoparathyroidism Ia (PHP-Ia) and PHP-Ib, and transient neonatal diabetes.

  • In vitro manipulation of embryos during assisted reproduction procedures might lead to imprinting defects in the offspring.

  • Abnormal expansion of a CGG repeat in the FMR1 gene, accompanied by its hypermethylation and silencing, leads to fragile X syndrome. By contrast, contraction and hypomethylation of a larger 3.3 kb repeat leads to facioscapulohumeral muscular dystrophy.

  • Mutations in the machinery that regulates DNA methylation patterns and chromatin structure also contribute to human disease. Mutations in DNMT3B and ATRX lead to immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome and Alpha-thalassemia/mental retardation syndrome, X-linked syndrome, respectively. Both disorders are characterized by localized disruptions in DNA methylation patterns.

  • The insulator/boundary proteins CCCTC-binding factor and BORIS, and the repression system known as RNAi, are probably involved in establishing and maintaining normal DNA methylation patterns.

Abstract

DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, a growing number of human diseases have been found to be associated with aberrant DNA methylation. The study of these diseases has provided new and fundamental insights into the roles that DNA methylation and other epigenetic modifications have in development and normal cellular homeostasis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: DNA methylation and cancer.
Figure 2: Regions involved in disease-associated genomic imprinting defects.
Figure 3: DNA methylation and diseases associated with repeat instability.
Figure 4: A model for the disruption of normal DNA methylation in cancer cells.

References

  1. Bird, A. DNA methylation patterns and epigenetic memory. Genes. Dev. 16, 6–21 (2002). An excellent review of DNA methylation in mammalian cells.

    CAS  PubMed  Google Scholar 

  2. Fischle, W., Wang, Y. & Allis, C. D. Binary switches and modification cassettes in histone biology and beyond. Nature 425, 475–479 (2003).

    CAS  PubMed  Google Scholar 

  3. Robertson, K. D. DNA methylation and chromatin — unraveling the tangled web. Oncogene 21, 5361–5379 (2002).

    CAS  PubMed  Google Scholar 

  4. Hendrich, B. & Tweedie, S. The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet. 19, 269–277 (2003).

    CAS  PubMed  Google Scholar 

  5. Mayer, W., Niveleau, A., Walter, J., Fundele, R. & Haaf, T. Demethylation of the zygotic paternal genome. Nature 403, 501–502 (2000). This paper demonstrates that active demethylation occurs during embryonic development in the absence of cell division.

    CAS  PubMed  Google Scholar 

  6. Yoder, J. A., Walsh, C. P. & Bestor, T. H. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 13, 335–340 (1997).

    CAS  PubMed  Google Scholar 

  7. Bird, A. CpG-rich islands and the function of DNA methylation. Nature 321, 209–213 (1986).

    CAS  PubMed  Google Scholar 

  8. Song, F. et al. Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc. Natl Acad. Sci. USA 102, 3336–3341 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Panning, B. & Jaenisch, R. DNA hypomethylation can activate Xist expression and silence X-linked genes. Genes. Dev. 10, 1991–2002 (1996).

    CAS  PubMed  Google Scholar 

  10. Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

    CAS  PubMed  Google Scholar 

  11. Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999). References 10 and 11 describe in detail the detrimental effects that loss of DNA methylation has on mouse embryonic development.

    CAS  PubMed  Google Scholar 

  12. Brown, R. & Strathdee, G. Epigenomics and epigenetic therapy of cancer. Trends Mol. Med. 8 (Suppl.), S43–S48 (2002).

    CAS  PubMed  Google Scholar 

  13. Novina, C. D. & Sharp, P. A. The RNAi revolution. Nature 430, 161–164 (2004).

    CAS  PubMed  Google Scholar 

  14. Shahbazian, M. D. & Zoghbi, H. Y. Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations. Curr. Opin. Neurol. 14, 171–176 (2001).

    CAS  PubMed  Google Scholar 

  15. Feinberg, A. P. & Tycko, B. The history of cancer epigenetics. Nature Rev. Cancer 4, 1–11 (2004).

    Google Scholar 

  16. Mertens, F., Johansson, B., Hoglund, M. & Mitelman, F. Chromosomal imbalance maps of malignant solid tumors: A cytogenetic survey of 3185 neoplasms. Cancer Res. 57, 2765–2780 (1997).

    CAS  PubMed  Google Scholar 

  17. Robertson, K. D. & Wolffe, A. P. DNA methylation in health and disease. Nature Rev. Genet. 1, 11–19 (2000).

    CAS  PubMed  Google Scholar 

  18. Widschwendter, M. et al. DNA hypomethylation and ovarian cancer biology. Cancer Res. 64, 4472–4480 (2004).

    CAS  PubMed  Google Scholar 

  19. De Smet, C., Lurquin, C., Lethe, B., Martelange, V. & Boon, T. DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Mol. Cell. Biol. 19, 7327–7335 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Nakamura, N. & Takenaga, K. Hypomethylation of the metastasis-associated S100A4 gene correlates with gene activation in human colon adenocarcinoma cell lines. Clin. Exp. Metastasis 16, 471–479 (1998).

    CAS  PubMed  Google Scholar 

  21. Akiyama, Y., Maesawa, C., Ogasawara, S., Terashima, M. & Masuda, T. Cell-type specific repression of the maspin gene is disrupted frequently by demethylation at the promoter region in gastric intestinal metaplasia and cancer cells. Am. J. Clin. Pathol. 163, 1911–1919 (2003).

    CAS  Google Scholar 

  22. Gupta, A., Godwin, A. K., Vanderveer, L., Lu, A. & Liu, J. Hypomethylation of the synuclein γ gene CpG island promotes its aberrant expression in breast and ovarian carcinoma. Cancer Res. 63, 664–673 (2003).

    CAS  PubMed  Google Scholar 

  23. Strichman-Almashanu, L. Z. et al. A genome-wide screen for normally methylated human CpG islands that can identify novel imprinted genes. Gen. Res. 12, 543–554 (2002).

    CAS  Google Scholar 

  24. Issa, J. -P. CpG island methylator phenotype in cancer. Nature Rev. Cancer 4, 988–993 (2004).

    CAS  Google Scholar 

  25. Chan, A. O.- O. et al. CpG island methylation in aberrant crypt foci of the colorectum. Am. J. Pathol. 160, 1823–1830 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Costello, J. F. et al. Aberrant CpG-island methylation has a non-random and tumor-type-specific patterns. Nature Genet. 25, 132–138 (2000). This paper represents one of the most comprehensive genome-wide scans for aberrant methylation in cancer and demonstrates just how widespread the defects are.

    Google Scholar 

  27. Laird, P. W. The power and the promise of DNA methylation markers. Nature Rev. Cancer 3, 253–266 (2003).

    CAS  Google Scholar 

  28. Feinberg, A. P., Cui, H. & Ohlsson, R. DNA methylation and genomic imprinting: insights from cancer into epigenetic mechanisms. Sem. Canc. Biol. 12, 389–398 (2002).

    CAS  Google Scholar 

  29. Reik, W. & Walter, J. Genomic imprinting: parental influence on the genome. Nature Rev. Genet. 2, 21–32 (2001).

    CAS  PubMed  Google Scholar 

  30. Klenova, E. M., Morse, H. C., Ohlsson, R. & Lobanenkov, V. V. The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. Sem. Canc. Biol. 449, 1–16 (2002).

    Google Scholar 

  31. Kanduri, C. et al. Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr. Biol. 10, 853–856 (2000). This paper shows that CTCF binding is methylation sensitive and provides important mechanistic insights into how cells distinguish between maternal and paternal alleles.

    CAS  PubMed  Google Scholar 

  32. Thakur, N. et al. An antisense RNA regulates the bidirectional silencing property of the Kcnq1 imprinting control region. Mol. Cell. Biol. 24, 7855–7862 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Schoenherr, C. J., Levorse, J. M. & Tilghman, S. M. CTCF maintains differential methylation at the Igf2/H19 locus. Nature Genet. 33, 66–69 (2003).

    CAS  PubMed  Google Scholar 

  34. Khosla, S., Dean, W., Brown, D., Reik, W. & Feil, R. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biol. Reprod. 64, 918–926 (2001).

    CAS  PubMed  Google Scholar 

  35. Behr, B. & Wang, H. Effects of culture conditions on IVF outcome. Eur. J. Obstet. Gynecol. Reprod. Biol. 115 (Suppl. 1), S72–S76 (2004).

    PubMed  Google Scholar 

  36. Dean, W. et al. Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proc. Natl Acad. Sci. USA 98, 13734–13738 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. De Baun, M. R., Niemitz, E. L. & Feinberg, A. P. Association of in vitro fertilization with Beckwith–Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am. J. Hum. Genet. 72, 156–160 (2003). References 34–37 show that in vitro culturing of embryos can lead to epigenetic defects in animals and that this might also have a role in humans.

    CAS  Google Scholar 

  38. Hao, Y., Crenshaw, T., Moulton, T., Newcomb, E. & Tycko, B. Tumour-suppressor activity of H19 RNA. Nature 365, 764–767 (1993).

    CAS  PubMed  Google Scholar 

  39. Moulton, T. et al. Epigenetic lesions at the H19 locus in Wilms' tumor patients. Nature Genet. 7, 440–447 (1994).

    CAS  PubMed  Google Scholar 

  40. Steenman, M. J. C. et al. Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumor. Nature Genet. 7, 433–439 (1994).

    CAS  PubMed  Google Scholar 

  41. Sakatani, T. et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 307, 1976–1978 (2005).

    CAS  PubMed  Google Scholar 

  42. Cui, H. et al. Loss of imprinting of insulin-like growth factor-II in Wilms' tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cancer Res. 61, 4947–4950 (2001).

    CAS  PubMed  Google Scholar 

  43. Nakagawa, H. et al. Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc. Natl Acad. Sci. USA 98, 591–596 (2001).

    CAS  PubMed  Google Scholar 

  44. Cui, H. et al. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res. 62, 6442–6446 (2002).

    CAS  PubMed  Google Scholar 

  45. Thompson, J. S., Reese, K. J., DeBaun, M. R., Perlman, E. J. & Feinberg, A. P. Reduced expression of the cyclin-dependent kinase inhibitor gene p57KIP2 in Wilms' tumor. Cancer Res. 56, 5723–5727 (1996).

    CAS  PubMed  Google Scholar 

  46. Yu, Y. et al. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Proc. Natl Acad. Sci. USA 96, 214–219 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Pedersen, I. S. et al. Frequent loss of imprinting of PEG1/MEST in invasive breast cancer. Cancer Res. 59, 5449–5451 (1999).

    CAS  PubMed  Google Scholar 

  48. Walter, J. & Paulsen, M. Imprinting and disease. Semin. Cell Dev. Biol. 14, 101–110 (2003).

    CAS  PubMed  Google Scholar 

  49. Lee, M. P. et al. Loss of imprinting of a paternally expressed transcript, with antisense orientation to KvLQT1, occurs frequently in Beckwith–Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Proc. Natl Acad. Sci. USA 96, 5203–5208 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kanduri, C. et al. A differentially methylated imprinting control region within the Kcnq1 locus harbors a methylation-sensitive chromatin insulator. J. Biol. Chem. 277, 18106–18110 (2002).

    CAS  PubMed  Google Scholar 

  51. Butler, M. G. Imprinting disorders: non-Mendelian mechanisms affecting growth. J. Pediatr. Endocrinol. Metab. 15, 1279–1288 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Weksberg, R. et al. Tumor development in the Beckwith–Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum. Mol. Genet. 10, 2989–3000 (2001).

    CAS  PubMed  Google Scholar 

  53. Diaz-Meyer, N. et al. Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith–Wiedemann syndrome. J. Med. Genet. 40, 797–801 (2005).

    Google Scholar 

  54. Goldstone, A. P. Prader–Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol. Metab. 15, 12–20 (2004).

    CAS  PubMed  Google Scholar 

  55. Nicholls, R. D. & Knepper, J. L. Genome organization, function, and imprinting in Prader–Willi and Angelman syndromes. Annu. Rev. Genomics Hum. Genet. 2, 153–175 (2001).

    CAS  PubMed  Google Scholar 

  56. Sutcliffe, J. S. et al. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nature Genet. 8, 52–58 (1994).

    CAS  PubMed  Google Scholar 

  57. Runte, M. et al. Comprehensive methylation analysis in typical and atypical PWS and AS patients with normal biparental chromosomes 15. Eur. J. Hum. Genet. 9, 519–526 (2001).

    CAS  PubMed  Google Scholar 

  58. Runte, M. et al. The IC-SNURF–SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum. Mol. Genet. 10, 2687–2700 (2001).

    CAS  PubMed  Google Scholar 

  59. Gerard, G., Hernandez, L., Wevrick, R. & Stewart, C. L. Disruption of the mouse necdin gene results in early post-natal lethality. Nature Genet. 23, 199–202 (1999).

    CAS  PubMed  Google Scholar 

  60. Tsai, T. F., Jiang, Y. H., Bressler, J., Armstrong, D. & Beaudet, A. L. Paternal deletion from Snrpn to Ube3a in the mouse causes hypotonia, growth retardation and partial lethality and provides evidence for a gene contributing to Prader–Willi syndrome. Nature Genet. 8, 1357–1364 (1999).

    CAS  Google Scholar 

  61. Saitoh, S. & Wada, T. Parent-of-origin specific histone acetylation and reactivation of a key imprinted gene locus in Prader–Willi syndrome. Am. J. Hum. Genet. 66, 1958–1962 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Lossie, A. C. et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J. Med. Genet. 38, 834–845 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Buiting, K., Lich, C., Cottrell, S., Barnicoat, A. & Horsthemke, B. A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp. Hum. Genet. 105, 665–666 (1999).

    CAS  PubMed  Google Scholar 

  64. Lalande, M. Imprints of disease at GNAS1. J. Clin. Inves. 107, 793–794 (2001).

    CAS  Google Scholar 

  65. Liu, J., Nealon, J. G. & Weinstein, L. S. Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB. Hum. Mol. Genet. 14, 95–102 (2005).

    CAS  PubMed  Google Scholar 

  66. Hayward, B. E. et al. Imprinting of the G s α gene GNAS1 in the pathology of acromegaly. J. Clin. Inves. 107, R31–R36 (2001).

    CAS  Google Scholar 

  67. Temple, I. K. & Shield, J. P. H. Transient neonatal diabetes, a disorder of imprinting. J. Med. Genet. 39, 872–875 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Arima, T. et al. A conserved imprinting control region at the HYMAI/ZAC domain is implicated in transient neonatal diabetes mellitus. Hum. Mol. Genet. 10, 1475–1483 (2001).

    CAS  PubMed  Google Scholar 

  69. Morison, I. M. & Reeve, A. E. A catalogue of imprinted genes and parent-of-origin effects in humans and animals. Hum. Mol. Genet. 7, 1599–1609 (1998). An excellent review detailing all known disorders in humans and animals that have a parent-of-origin bias.

    CAS  PubMed  Google Scholar 

  70. Lewis, A. & Murrell, A. Genomic imprinting: CTCF protects the boundaries. Curr. Biol. 14, R284–R286 (2004).

    CAS  PubMed  Google Scholar 

  71. Everett, C. M. & Wood, N. W. Trinucleotide repeats and neurodegenerative disease. Brain 127, 2385–2405 (2004).

    CAS  PubMed  Google Scholar 

  72. Cleary, J. D. & Pearson, C. E. The contribution of cis-elements to disease-associated repeat instability: clinical and experimental evidence. Cytogenet. Genome Res. 100, 25–55 (2003).

    CAS  PubMed  Google Scholar 

  73. Crawford, D. C., Acuna, J. M. & Sherman, S. L. FMR1 and the fragile X syndrome: human genome epidemiology review. Genet. Med. 3, 359–371 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Sutherland, G. R. Rare fragile sites. Cytogenet. Genome Res. 100, 77–84 (2003).

    CAS  PubMed  Google Scholar 

  75. Jin, P., Alisch, R. S. & Warren, S. T. RNA and microRNAs in fragile X mental retardation. Nature Cell Biol. 6, 1048–1053 (2004).

    CAS  PubMed  Google Scholar 

  76. Hagerman, R. J. et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57, 127–130 (2001).

    CAS  PubMed  Google Scholar 

  77. Oberle, I. et al. Instability of a 550-base pair segment and abnormal methylation in fragile X syndrome. Science 252, 1097–1102 (1991).

    CAS  PubMed  Google Scholar 

  78. Coffee, B., Zhang, F., Ceman, S., Warren, S. T. & Reines, D. Histone modifications depict an aberrantly heterochromatinized FMR1 gene in fragile X syndrome. Am. J. Hum. Genet. 71, 923–932 (2002).

    PubMed  PubMed Central  Google Scholar 

  79. Sarafidou, T. et al. Folate-sensitive fragile site FRA10A is due to an expansion of a CGG repeat in a novel gene, FRA10AC1, encoding a nuclear protein. Genomics 84, 69–81 (2004).

    CAS  PubMed  Google Scholar 

  80. van Overveld, P. G. M. et al. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nature Genet. 34, 315–317 (2003).

    Google Scholar 

  81. Rijkers, T. et al. FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients. J. Med. Genet. 41, 826–836 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Gabellini, D., Green, M. R. & Tupler, R. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell 110, 339–348 (2002).

    CAS  PubMed  Google Scholar 

  83. Jiang, G. et al. Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q. Hum. Mol. Genet. 12, 2909–2921 (2003).

    CAS  PubMed  Google Scholar 

  84. Steinbach, P., Glaser, D., Vogel, W., Wolf, M. & Schwemmle, S. The DMPK gene of severely affected myotonic dystrophy patients is hypermethylated proximal to the largely expanded CTG repeat. Am. J. Hum. Genet. 62, 278–285 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Filippova, G. N. et al. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nature Genet. 28, 335–343 (2001).

    CAS  PubMed  Google Scholar 

  86. Saveliev, A., Everett, C., Sharpe, T., Webster, Z. & Festenstein, R. DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing. Nature 422, 909–913 (2003).

    CAS  PubMed  Google Scholar 

  87. Edamura, K. N., Leonard, M. R. & Pearson, C. E. Role of replication and CpG methylation in fragile X syndrome CGG deletions in primate cells. Am. J. Hum. Genet. 76, 302–311 (2005).

    CAS  Google Scholar 

  88. Gorbunova, V., Seluanov, A., Mittelman, D. & Wilson, J. H. Genome-wide demethylation destabilizes CTG•CAG trinucleotide repeats in mammalian cells. Hum. Mol. Genet. 13, 2979–2989 (2004).

    CAS  PubMed  Google Scholar 

  89. Reik, W., Maher, E. R., Morrison, P. J., Narding, A. E. & Simpson, S. A. Age of onset in Huntington's disease and methylation at D4S95. J. Med. Genet. 30, 185–188 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Smith, S. S., Laayoun, A., Lingeman, R. G., Baker, D. J. & Riley, J. Hypermethylation of telomere-like foldbacks at codon 12 of the human c-Ha-ras gene and the trinucleotide repeat of the FMR-1 gene of fragile X. J. Mol. Biol. 243, 143–151 (1994).

    CAS  PubMed  Google Scholar 

  91. Handa, V., Saha, T. & Usdin, K. The fragile X syndrome repeats form RNA hairpins that do not activate the interferon-inducible protein kinase, PKR, but are cut by dicer. Nucleic Acids Res. 31, 6243–6248 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Klippel, J. H. Systemic lupus erythematosus: demographics, prognosis, and outcome. J. Rheumatol. 24, 67–71 (1997).

    Google Scholar 

  93. Richardson, B. DNA methylation and autoimmune disease. Clin. Immunol. 109, 72–79 (2003).

    CAS  PubMed  Google Scholar 

  94. Richardson, B. et al. Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 33, 1665–1673 (1990).

    CAS  PubMed  Google Scholar 

  95. Quddus, J. et al. Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J. Clin. Inves. 92, 38–53 (1993).

    CAS  Google Scholar 

  96. Lu, Q. et al. Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis Rheum. 46, 1282–1291 (2003).

    Google Scholar 

  97. Oelke, K. et al. Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis Rheum. 50, 1850–1860 (2004).

    CAS  PubMed  Google Scholar 

  98. Sekigawa, I. et al. DNA methylation in systemic erythematosus. Lupus 12, 79–85 (2003).

    CAS  PubMed  Google Scholar 

  99. Scheinbart, L. S., Johnson, M. A., Gross, L. A., Edelstein, S. R. & Richardson, B. C. Procainamide inhibits DNA methyltransferase in a human T cell line. J. Rheum. 18, 530–540 (1991).

    CAS  PubMed  Google Scholar 

  100. Deng, C. et al. Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signalling. Arthritis Rheum. 48, 746–756 (2003).

    CAS  PubMed  Google Scholar 

  101. Smeets, D. F. et al. ICF syndrome: a new case and review of the literature. Hum. Genet. 94, 240–246 (1994).

    CAS  PubMed  Google Scholar 

  102. Ehrlich, M. The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. Clin. Immunol. 109, 17–28 (2003).

    CAS  PubMed  Google Scholar 

  103. Franceschini, P. et al. Variability of clinical and immunological phenotype in immunodeficiency-centromeric instability-facial anomalies syndrome. Eur. J. Pediatr. 154, 840–846 (1995).

    CAS  PubMed  Google Scholar 

  104. Tuck-Muller, C. M. et al. DNA hypomethylation and unusual chromosome instability in cell lines from ICF patients. Cytogenet. Cell Genet. 89, 121–128 (2000).

    CAS  PubMed  Google Scholar 

  105. Xu, G. -L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999).

    CAS  PubMed  Google Scholar 

  106. Hansen, R. S. et al. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl. Acad. Sci. USA 96, 14412–14417 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Gowher, H. & Jeltsch, A. Molecular enzymology of the catalytic domains of the Dnmt3a and Dnmt3b DNA methyltransferases. J. Biol. Chem. 277, 20409–20414 (2002).

    CAS  PubMed  Google Scholar 

  108. Jiang, Y. L. et al. DNMT3B mutations and DNA methylation defect define two types of ICF syndrome. Hum. Mut. 25, 56–63 (2005).

    CAS  PubMed  Google Scholar 

  109. Kondo, T. et al. Whole-genome methylation scan in ICF syndrome: hypomethylation of non-satellite DNA repeats D4Z4 and NBL2. Hum. Mol. Genet. 9, 597–604 (2000).

    CAS  PubMed  Google Scholar 

  110. Tao, Q. et al. Defective de novo methylation of viral and cellular DNA sequences in ICF syndrome cells. Hum. Mol. Genet. 11, 2091–2102 (2002).

    CAS  PubMed  Google Scholar 

  111. Hansen, R. S. et al. Escape from gene silencing in ICF syndrome: evidence for advanced replication time as a major determinant. Hum. Mol. Genet. 9, 2575–2587 (2000).

    CAS  PubMed  Google Scholar 

  112. Ehrlich, M. DNA hypomethylation, cancer, the immunodeficiency, centromeric region instability, facial anomalies syndrome and chromosomal rearrangements. J. Nutr. 132, S2424–S2429 (2002).

    Google Scholar 

  113. Ehrlich, M. et al. DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphomagenesis genes. Hum. Mol. Genet. 10, 2917–2931 (2001).

    CAS  PubMed  Google Scholar 

  114. Geiman, T. M. et al. DNMT3B interacts with hSNF2H chromatin remodeling enzyme, HDACs 1 and 2, and components of the histone methylation system. Biochem. Biophys. Res. Commun. 318, 544–555 (2004).

    CAS  PubMed  Google Scholar 

  115. Geiman, T. M. et al. Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery. Nucleic Acids Res. 32, 2716–2729 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Bai, S. et al. DNA methyltransferase 3b regulates nerve growth factor-induced differentiation of PC12 cells by recruiting histone deacetylase 2. Mol. Cell. Biol. 25, 751–766 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Havas, K., Whitehouse, I. & Owen-Hughes, T. ATP-dependent chromatin remodeling activities. Cell. Mol. Life Sci. 58, 673–682 (2001).

    CAS  PubMed  Google Scholar 

  118. Gibbons, R. J. et al. Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. Nature Genet. 17, 146–148 (1997).

    CAS  PubMed  Google Scholar 

  119. Cardoso, C. et al. ATR-X mutations cause impaired nuclear location and altered DNA binding properties of the XNP/ATR-X protein. J. Med. Genet. 37, 746–751 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Tang, J. et al. A novel transcription regulatory complex containing death domain-associated protein and the ATR-X syndrome protein. J. Biol. Chem. 279, 20369–20377 (2004).

    CAS  PubMed  Google Scholar 

  121. Ishov, A. M., Vlafimirova, O. V. & Maul, G. G. Heterochromatin and ND10 are cell-cycle regulated and phosphorylation-dependent alternate nuclear sites of the transcription repressor Daxx and SWI/SNF protein ATRX. J. Cell. Sci. 117, 3807–3820 (2004).

    CAS  PubMed  Google Scholar 

  122. Xue, Y. et al. The ATRX syndrome protein forms a chromatin-remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies. Proc. Natl Acad. Sci. USA 100, 10635–10640 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Gibbons, R. J. et al. Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the patterns of DNA methylation. Nature Genet. 24, 368–371 (2000).

    CAS  PubMed  Google Scholar 

  124. Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nature Rev. Genet. 3, 415–428 (2002).

    CAS  PubMed  Google Scholar 

  125. Filippova, G. N. et al. Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CpG methylation during early development. Dev. Cell 8, 31–42 (2005).

    CAS  PubMed  Google Scholar 

  126. Loukinov, D. I. et al. BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc. Natl Acad. Sci. USA 99, 6806–6811 (2002). The first in-depth characterization of the CTCF paralogue BORIS and a demonstration of the mutually exclusive expression of these two proteins in normal tissues.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Verdel, A. et al. RNAi-mediated targeting of heterochromatin by the RITS complex. Science 303, 672–676 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Noma, K. -i. et al. RITS acts in cis to promote RNA interference-mediated transcriptional and post-transcriptional silencing. Nature Genet. 36, 1174–1180 (2004).

    CAS  PubMed  Google Scholar 

  129. Schramke, V. & Allshire, R. Hairpin RNAs and retrotransposon LTRs effect RNAi and chromatin-based gene silencing. Science 301, 1069–1073 (2003).

    CAS  PubMed  Google Scholar 

  130. Motamedi, M. R. et al. Two RNAi complexes, RITS and RDRC, physically interact and localize to noncoding centromeric RNAs. Cell 119, 789–802 (2004). References 127–130 provided the first direct, mechanistic evidence for how the RNAi machinery can target transcriptional repression back to heterochromatic repeat regions of the genome.

    CAS  PubMed  Google Scholar 

  131. Kawasaki, H. & Taira, K. Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature 431, 211–217 (2004).

    CAS  PubMed  Google Scholar 

  132. Rudert, F., Bronner, S., Garnier, J. M. & Dolle, P. Transcripts from opposite strands of γ satellite DNA are differentially expressed during mouse development. Mamm. Genome 6, 76–83 (1995).

    CAS  PubMed  Google Scholar 

  133. Lehnertz, B. et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr. Biol. 13, 1192–1200 (2003).

    CAS  PubMed  Google Scholar 

  134. Tufarelli, C. et al. Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nature Genet. 34, 157–165 (2003).

    CAS  PubMed  Google Scholar 

  135. Shendure, J. & Church, G. M. Computational discovery of sense–antisense transcription in the human and mouse genomes. Genome Biol. 3, 1–14 (2003).

    Google Scholar 

  136. Lavorgna, G. et al. In seach of antisense. Trends Biochem. Sci. 29, 88–94 (2004).

    CAS  PubMed  Google Scholar 

  137. Mukhopadhyay, R. et al. The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide. Gen. Res. 14, 1594–1602 (2004).

    CAS  Google Scholar 

  138. Fedoriw, A. M., Stein, P., Svoboda, P., Schultz, R. M. & Bartolomei, M. S. Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting. Science 303, 238–240 (2004).

    CAS  PubMed  Google Scholar 

  139. Rand, E., Ben-Porath, I., Keshet, I. & Cedar, H. CTCF elements direct allele-specific undermethylation at the imprinted H19 locus. Curr. Biol. 14, 1007–1012 (2004).

    CAS  PubMed  Google Scholar 

  140. Rasko, J. E. J. et al. Cell growth inhibition by the multifunctional multivalent zinc-finger factor CTCF. Cancer Res. 61, 6002–6007 (2001).

    CAS  PubMed  Google Scholar 

  141. Filippova, G. N. et al. Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter its DNA-binding specificity. Cancer Res. 62, 48–52 (2002).

    CAS  PubMed  Google Scholar 

  142. Wright, V. C., Schieve, L. A., Reynolds, M. A., Jeng, G. & Kissin, D. Assisted reproductive technology surveillance — United States, 2001. MMWR Surveill Summ. 53, 1–20 (2004).

    PubMed  Google Scholar 

  143. Cox, G. F. et al. Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am. J. Hum. Genet. 71, 162–164 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Gicquel, C. et al. In vitro fertilization may increase the risk of Beckwith–Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am. J. Hum. Genet. 72, 1338–1341 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Reik, W., Dean, W. & Walter, J. Epigenetic reprogramming in mammalian development. Science 293, 1089–1093 (2001).

    CAS  PubMed  Google Scholar 

  146. Li, E., Beard, C. & Jaenisch, R. Role for DNA methylation in genomic imprinting. Nature 366, 362–365 (1993).

    CAS  PubMed  Google Scholar 

  147. De Chiara, T. M., Robertson, E. J. & Efstratiadis, A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64, 849–859 (1991).

    CAS  Google Scholar 

  148. Barker, D. J. et al. Fetal nutrition and cardiovascular disease in adult life. Lancet 341, 938–941 (1993).

    CAS  PubMed  Google Scholar 

  149. Mann, M. R. W. et al. Selective loss of imprinting in the placenta following preimplantation development in culture. Development 131, 3727–3735 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I apologize to those whose work could not be cited owing to space limitations. Work in the author's lab is supported by the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Shands Cancer Center, University of Florida, Box 100245, 1600 S.W. Archer Road, Gainesville, 32610, Florida, USA

    Keith D. Robertson

Authors
  1. Keith D. Robertson
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Related links

Related links

DATABASES

Entrez gene

ATP10C

ATRX

BORIS

CDKN1C

CTCF

DAXX

DIRAS3

Dnmt1

Dnmt3a

Dnmt3b

FMR1

FRAXE

FRAXF

FRA10A

FRA11B

FRA16A

FRG1

FRG2

GNAS

HYMAI

IGF2

KCNQ1

KCNQ1OT1

MEST

PLAGL1

S100A4

SERPINB5

SNCG

SNRPN

SNURF

UBE3A

Omim

Albright hereditary osteodystrophy

alpha-thalassemia/mental retardation syndrome, X-linked

Angelman syndrome

Beckwith–Wiedemann syndrome

facioscapulohumeral muscular dystrophy

fragile X syndrome

immunodeficiency, centromeric instability and facial anomalies syndrome

Prader–Willi syndrome

pseudohypoparathyroidism Ib

Rett syndrome

transient neonatal diabetes mellitus

FURTHER INFORMATION

The DNA methylation database

The DNA methylation society

Human Epigenome Project

The M. D. Anderson Cancer Center DNA Methylation in Cancer web site

The Genomic Imprinting Website

MRC Mammalian Genetics Unit Mouse Imprinting web site

CITE: Candidate Imprinted Transcript from gene Expression database

The DNMT3Bbase mutation registry for ICF syndrome

Glossary

CPG ISLAND

A genomic region of ∼1 kb that has a high G–C content, is rich in CpG dinucleotides and is usually hypomethylated.

TRANSCRIPTIONAL INTERFERENCE

Repression of one transcriptional unit by another such unit that is linked in cis.

RESTRICTION LANDMARK GENOMIC SCANNING

(RLGS). A genome-wide method for analyzing the DNA methylation status of CpG islands. Radiolabelled fragments obtained by digestion with NotI (a methylation-sensitive restriction enzyme) are separated by two-dimensional gel electrophoresis, allowing differentiation between methylated and unmethylated regions.

ENHANCER

A regulatory DNA element that usually binds several transcription factors and can activate transcription from a promoter at great distance and in an orientation-independent manner.

UNIPARENTAL DISOMY

Inheritance of a chromosome or chromosome region from a single parent.

BALANCED TRANSLOCATION

A condition in which two pieces of chromosomal material have switched places, but the correct number of chromosomes has been maintained.

UBIQUITIN–PROTEASOME DEGRADATION PATHWAY

Degradation pathway in which a protein that has been post-translationally modified with several ubiquitin polypeptides is targeted for destruction to the proteasome, a large cytosolic protein complex with several proteolytic activities.

CHROMOGRANINS

A group of acidic, soluble, secretory proteins that are produced by neurons and neuroendocrine cells.

OKAZAKI FRAGMENTS

Short pieces of DNA that are synthesized on the lagging strand at the replication fork.

FOLATE-SENSITIVE FRAGILE SITE

A region of chromatin that fails to compact normally during mitosis and that can be observed after culturing cells in media that is deficient in folic acid and thymidine.

RNAI

The process whereby double-stranded RNAs are cleaved into 21–23 nucleotide duplexes termed small interfering RNAs, leading to inhibition of expression of genes that contain a complementary sequence.

DICER

A ribonuclease that processes dsRNAs to ∼21 nucleotide siRNAs (for RNAi) or excises microRNAs from their hairpin precursors.

CD4+ T CELL

Also known as a helper T cell. Initiates both antibody production by B cells and stimulates the activation of other immune cells, such as macrophages, after recognizing a portion of a protein antigen on the surface of an antigen presenting cell.

ADOPTIVE TRANSFER

The process of conferring immunity to an individual by transferring cells or serum from another individual that has been immunized with a specific antigen.

SYNGENEIC MACROPHAGES

macrophages (immune cells that engulf foreign particles) that are transferred between genetically identical mice.

LYMPHOBLASTOID CELL LINE

Immortalized B cell line created by infecting primary B cells with Epstein-Barr virus.

SNF2-LIKE PROTEINS

ATP-dependent chromatin remodelling enzymes that contain a region homologous to an extended family of proteins that include known RNA and DNA helicases.

PML BODIES

Dot-like structures in the nucleus of most mammalian cells. These were originally defined by the localization of the PML protein, which is involved in transcriptional regulation.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Robertson, K. DNA methylation and human disease. Nat Rev Genet 6, 597–610 (2005). https://doi.org/10.1038/nrg1655

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1655

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing